Retinal vascular occlusions are a leading cause of blindness in elderly patients. While younger patients may develop this disease (referred to as papillophlebitis in younger patients), most occlusions occur in individuals over the age of 50.
A retinal vascular occlusion is characterized by a fully or partially occluded retinal vessel that limits the flow of blood through the retinal tissue. Blood is delivered to the retina through the arteries, which then lead to the capilliaries and then the venous system beginning with smaller veins and ending with larger veins, and finally to the central retinal vein. Occlusion in any of these retinal vessels leads to a build-up of pressure, which may lead to hemorrhages and also leakage of fluid and other constituents of blood.
The site of the occlusion typically occurs on the venous side and may occur in either the branch vessel (branch retinal vein occlusion—BRVO) or in the central retinal vein (central retinal vein occlusion—CRVO). The occlusion site determines the extent of the hemorrhage: a small vein branch occlusion to a quadrantic occlusion affects one fourth of the retina, a hemispheric or hemi-retinal occlusion affects one half of the retina, and a central retinal vein occlusion (CRVO) affects the entire retina.
Retinal venous occlusive disease can affect vision in many ways. The retina is made up seven layers of cells that convert light signals into a neural signals. The cells that transmit to the brain are the ganglion cells. In order for the ganglion cells to function properly, they require an adequate flow of blood. When retinal vessels are blocked, the area of the retina supplied by that vessel has poor blood flow, which results in sub-optimal performance by the local ganglion cells and even death of these local ganglion cells. In some severe cases, poor blood flow resulting from retinal vascular occlusions can also lead to the development of abnormal new vessels (neovascularization). These new vessels are fragile and leak fluid and blood, which damages cells in the retina. In severe cases of neovacularization, the new abnormal blood vessels may pull on the retina, leading to retinal detachment. In very serious cases, the eye may develop neovascular glaucoma, in which fluid outflow channels in the eye are blocked, placing the eye is under very high pressure. This may result in severe vision loss, pain and even loss of the eye itself.
Although retinal venous occlusive disease is a highly prevalent disease with serious consequences, treatment options remain limited.
The Central Vein Occlusion Study provides guidelines to treat the sequelae of the venous obstruction rather than the underlying occlusive event. (““Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group” Arch. Qphthalmol, 1997:115:486–91. Several recent efforts have had the goal to re-establish vent outflow. One such effort proposes to bypass the occluded vein by a laser or surgically-induced chorioretinal anastomosiss. (Fekrat S. de J E, Jr. “Chorioretinal venous anastomosis for central retinal vein occlusion transvitreal venipuncture” Ophthalmic Surg. Lasers, 1995; 113:456–62; McAllister I L, Constable l J. “Laser-induced chorioretinal venous anastomosis for treatment of nonischemic centrl retinal vein occlusion” Arch. Ophthalmol, 1995:113:456–62.) This approach does not attempt to re-establish the normal venous return pathway from the retina. Moreover, it has had limited success and can lead to uncontrolled choroidal neovascularization resulting in vitreous hemorrhage and tractional retinal detachment. (McAllister I L, Douglas J P, Constable l J, Yu D Y. “Laser induced chorioretinal venous anastomosis for nonischemic central retinal vein occlusion: evaluation of the complications and their risk factors” Am. J Ophthalmol, 1998; 126:219–29). Similarly, the benefit of other approaches remain unproven such as, for example, the use of platelet inhibitors (Glacet-Bernard A. Coscas G. Chabanel A, Zourdani A, Lelong F. Samama M M. “A randomized, double-masked study on the treatment of retinal vein occlusion with troxerutin” Am. J. Ophthalmol,. 1994; 118:421–29), steroids (Beaumont P E, Kang H K. “Ophthalmodynamometry and corticosteroids in central retinal vein occlusion” Aust. N. Z. J. Ophthalmol, 1994:22:271–74), hemodilution (Wolf S, Arend O, Bertram B, Remky A, Schulte K, Wald K J et al. “Hemodilution therapy in central retinal vein occlusion, One-year results of a prospective randomized study” Graefes Arch. Clin. Exp. Ophthalmol, 1994:232:33–39; Luckie A P, Wroblewski J J, Hamilton P, Bird A C, Sanders M, Slater N et al. “A randomised prospective study of outpatient haemodilution for central retinal vein obstruction” Aust N. Z. J Ophthalmol, 1996; 24:223 32), or optic nerve sheath decompression (Dev S, Buckley E G. “Optic nerve sheath decompression for progressive central retinal vein occlusion” Ophthalmic Surg. Lasers, 1999; 30:181–84).
A histopathologic study of 29 human eyes with ischemic central retinal vein occlusions concluded that the underlying cause of venous occlusions was a venous thrombosis in the region of lamina cribosa. (Green W R, Chan C C, Hutchins G M, Terry J M. “Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases” Trans. Am. Ophthalmol Soc., 1981:79:371–422). Clot dissolving drugs called thrombolytic agents exist and are used successfully on other occluded vascular networks. Because thrombolytics are effective in treating venous thrombosis elsewhere in the body, the idea of systemic administration of these drugs for the treatment of retinal venous occlusions is attractive. However, studies involving the systemic use of thrombolytics to treat central retinal vein occlusions have not been substantiated. (See, e.g. Elman M J. “Thrombolytio therapy for central retinal vein occlusion: results of a pilot study” Trans. Am. Ophthalmol Soc., 1998; 94:471–504; Kohner E M, Pettit J E, Hamilton A M, Bulpitt C J, Dollery C T. “Streptokinase in central retinal vein occlusion: a controlled clinical trial” Br. Med. J., 1976; 1:550–53; Hattenbach L O. “Systemic lysis therapy in retinal vascular occlusions” Ophthalmologe, 1998 95:568–75; Hattenbach L O, Wellermann G. Steinkarnp G W, Scharrer I, Koch F H, Ohrloff C. “Visual outcome after treatment with low-dose recombinant tissue plasminogen activator or hemodilution in ischemic central retinal vein occlusion” Ophthalmologe, 1998 95:568–75; Hattenbach L O, Wellermann G. Steinkarnp G W, Scharrer I, Koch F H, Ohrloff C. “Visual outcome after treatment with low-dose recombinant tissue plasminogen activator or hemodilution in ischemic central retinal vein occlusion” Ophthalmologica, 1999; 213; 360–66). The vasculature of the retina is unique, consisting of very long vessels emanating from and returning to a single point of entry in the optic verve. When presented with a static column of blood, thrombolytic agents delivered systemically are not able to diffuse through the vessels and arrive at the clot site in sufficient doses to dissolve the clot. If the systemic does is increased to a level that may potentially dissolve the clot, hemorrhage and other complications including stroke and death may occur. Thus, the potential promise of systemic thrombolysis must be soberly balanced with the risk of a life-threatening central nervous system or gastrointestinal hemorrhage.
An alternate method of administering thrombolytic therapy is to deliver the drug locally at or near the site of the occluded retinal vein by means of a microcatheter placed in the affected retinal vein. The idea of retinal vein catheterization for local intravascular thrombolytic delivery is not new and is found in the literature since at least 1987. (See, e.g. Allf B E, de J E, Jr. “In vivo cannulation of retinal vessels” Dev. Ophthalmol, 1987; 225:221–25; Cunha-Vaz J G, Murta J N, Proenca R D. “Micropuncture of retinal vessels” Dev. Ophthalmol, 1989; 18:90–94; Glucksberg M R, Dunn R, Glebs C P. “In vivo micropuncture of retinal vessels” Graefes Arch. Clin. Exp. Ophthalmol, 1993; 231:405–07; Weiss J N. “Treatment of central retinal vein occlusion by injection of tissue plasminogen activator into a retinal vein” Am. J Ophthalmol 1998; 126:142–44; Tang W M, Han D P. “A study of surgical approaches to retinal vascular occlusions” Arch. Ophthalmol, 2000:11 8:136–43; Weiss J N. “Retinal surgery for treatment of central retinal vein occlusion” Ophthalmic Surg. Lasers, 2000; 31:162–65). This approach has the theoretical advantage of allowing local infusion of a significantly smaller volume of a highly concentrated thrombolytic, thus reducing the systemic risk of a hemorrhage and reducing the risk of inducing a systemic fibrinolytic state.
However, the technique and instrumentation required to reliably insert a cannula into the lumen of a retinal vessel has been daunting. Further, as is the case for effective thrombolysis elsewhere in the body, the thrombolytic cascade of TPA, streptolinase or urikinase takes about 30 minutes to complete. Thus, the thrombolytic must be infused at least 30 minutes if not longer to be effective. (See. e.g. Goldhaber S Z. “Thrombolytic therapy” Adv. Intern. Med, 1999; 44:311–25; Heinz M, Theiss W. “Thrombolytic therapy of venous thromboses” Internist (Berl), 1996:37:567–73; Gulba D C, Bode C, Runge M S, Huber K. “Thrombolytic agents—an overview” Ann. Hematal, 1996; 73 Suppl 1:S9–27; Kandarpa K. “Catheter-directed thrombolysis of peripheral arterial occlusions and deep vein thrombosis” Thromb. Haemost., 1999; 82:987–96; Comerota A J, Katz M L, White J V. “Thrombolytic therapy for acute deep venous thrombosis: how much is enough?” Cardiovasc. Surg., 1996; 4:101–04).
The need for a long-term infusion into a retinal vein and the manual dexterity required to cannulate vessels of diameters as small as the retinal vein has led to the use of a rigid cannulae held in place by hand or with the use of a robot or a micromanipulator, which provide a mechanical aid to keep the instrument in place during and after the retinal venous puncture. (See. e.g. Goldhaber S Z. “Thrombolytic therapy” Adv. Intern. Med., 1999; 44:311–25; Heinz M, Theiss W. “Thrombolytic therapy of venous thromboses” Internist (Berl), 1996:37:567–73; Gulba D C, Bode C, Runge M S, Huber K. “Thrombolytic agents—an overview” Ann. Hematal., 1996; 73 Suppl 1:S9–27; Kandarpa K. “Catheter-directed thrombolysis of peripheral arterial occlusions and deep vein thrombosis” Thromb. Haemost., 1999; 82:987–96; Comerota A J, Katz M L, White J V. “Thrombolytic therapy for acute deep venous thrombosis: how much is enough?” Cardiovasc, Surg., 1996; 4:101–04; Allf B E, de J E, Jr. “In vivo cannulation of retinal vessels” Dev. Ophthalmol, 1987; 225:221–25; Cunha-Vaz J G, Murta J N, Proenca R D. “Micropuncture of retinal vessels” Dev. Ophthalmol, 1989; 18:90–94; Glucksberg M R, Dunn R, Glebs C P. “In vivo micropuncture of retinal vessels” Graefes Arch. Clin. Exp. Ophthalmol, 1993; 231:405–07; Weiss J N. “Treatment of central retinal vein occlusion by injection of tissue plasminogen activator into a retinal vein” Am. J Ophthalmol, 1998; 126:142–44).
For example, some prior attempts have concentrated on using rigid boriscilicate glass or stainless steel micropipettes held either by hand or with a mechanical micromanipulator or robot. However, performing this task by hand is difficult because the pipettes are inflexible and must be held precisely within the lumen of the vessel (approximately 0.1 mm). Human tremor and involuntary motions make this extremely difficult. Short-term canulations using a high-resolution endoscope for increased intraoperative visibility has been demonstrated (Hazma H. S., Humayun M. S., Jensen P. S., Shelly T., Shoukas A. and De Juan E., Jr. “Endoscopic guided hand-held cannulation of the retinal veins in-vivo” Invest Ophthalmol Vis. Sci. (abstract), 1999) and successful longer-term cannulations of the retinal vessels have been reported numerous times using a micromanipulator and a rigid micropipette. (Alf B. E., de Juan E., Jr. “In vivo cannulation of retinal vessels” Graefes Arch Clin. Exp. Ophthalmol, 1987; 225:21–225; Gluckberg M. R., Dunn R., Giebs C. “In vivo micropuncture of retinal vessels” Graefes Arch. Clin. Exp. Ophthalmol, 1993; 231:405–407; Jensen P. S., Grace K. W., Attariwala R., Colgate J. E., Glucksberg M. R. “Toward robot-assisted vascular microsurgery in the retina” Graefes Arch. Clin. Exp. Ophthalmol, 1997; 235:696–701; Weiss J. N., “Treatment of central retinal vein occlusion by injection of tissue plasminogen activator into a retinal vein” Am. J. Ophthalmol, 1998; 126:142–144). However, micromanipulators are complex, expensive and cumbersome to use in a surgical setting for the level of stability required. Further, micromanipulators also require that the head and eye of the patient be fixed with respect to the manipulator, typically accomplished by using eye rings, sutures, head straps, and other such physical restraints. Without such physical restraints, the infusion time allowed was relatively short (bolus injection). Further, even with such physical restraints, the rigid nature of the micropipettes used in these studies make it extremely difficult, if not impossible, to keep the tip of the pipette within the lumen of the vessel during the entire 30 minute drug delivery protocol. A micron scale motion of either the patient, the micropipette, the manipulator or the surgeon may cause the pipette to be dislodged.
Further, while these prior techniques demonstrate that vessel cannulation is possible in both laboratory and surgical settings using a mechanical manipulator (Weiss J. N., “Treatment of central retinal vein occlusion by injection of tissue plasminogen activator into a retinal vein” Am. J. Ophthalmol, 1998; 126:142–144), there is no technique to date that can be satisfactorily implemented in a surgical setting without these devices. Primary concerns are the cumbersome equipment required for cannulation and the lengthy infusion times associated with the thrombylitic therapy.
Thus, what is needed is a surgical device and method of use that allows infusion into a retinal vein for extended periods of time without the need for the surgeon, a robot, a micromanipulator or other holding devices to hold the surgical device in place during the infusion. What is further needed is a device that does not require rigidly fixating the eye to an eye ring during such long-term infusion. What is further needed is a device and method that may be suitably implemented in a surgical setting